The long-term objective of our investigations is to examine how, where and when the pharmacokinetics of organic nitrates may relate to their pharmacologic and therapeutic effects. The organic nitrates are used in a broad spectrum of cardiovascular diseases, and are still the first-line therapeutic agents against which the effectiveness of other vasodilators are judged. The organic nitrates also possess a number of unusual pharmacokinetic features, and they serve as useful model compounds for the study of other drugs which are rapidly cleared from the body. Our focus on the vascular pharmacokinetics of organic nitrates has proven to be a useful investigative approach in the understanding of nitrate action. In this proposal, our main goals are to utilize this approach in an examination of the implications of the mode of dosing (i.e., whether continuous or intermittent) on vascular nitrate activity and pharmacokinetics, and in an assessment of the usefulness of nitrate metabolites and thiol compounds in enhancing nitrate action. Through the studies proposed, we hope to achieve a better understanding of the pharmacokinetic determinants of nitrate action and to evolve a rational approach to the optimization of dosage regimens for these drugs. Our specific aims are (i) to examine whether the systemic clearance of nitroglycerin is limited by the cardiac output, (ii) to investigate the pharmacokinetics of nitroglycerin in blood vessels of various morphologies as functions of dosage regimen and degree of nitrate tolerance, (iii) to study the role of nitrate metabolites in vascular tolerance, (iv) to examine whether metabolite interaction occurs during hepatic extraction of organic nitrates, and (v) to explore the potential of systemically administered thiol compounds for imporving nitrate therapy.